CAN NICOTINE ACTUALLY HAVE A GOOD SIDE?
It gets people hooked on cigarettes, but researchers hope that nicotine
and related compounds will have therapeutic uses.

Nicotine is rightly reviled because of its association with smoking and
addiction. But new research has uncovered that the rogue substance has
a wide range of effects on the brain, which may include some healing properties.
Scientists are testing nicotine and related compounds as treatments for
Alzheimers disease, Parkinsons disease, attention deficit
hyperactivity disorder (ADHD), and other conditions.

Self-medicating with cigarettes

The interest in nicotines therapeutic potential started in the
1980s. Several population based studies found that smokers had lower rates
of Parkinsons disease than nonsmokers. Epidemiolo­gists also
validated what many mental health practitioners have long noticed: The
smoking rate among people with schizophrenia, depression, and anxiety
disorders is far higher than average. Its widely believed that people
with certain mental health problems are self-medicating with cigarettes
because the nicotine helps their minds function better.

A most rewarding experience

Tobacco  particularly when smoked  is highly addictive. The
cigarette sends the nicotine straight to the lungs, where its absorbed
by the blood, carried to the heart, and pumped up to the brain. One aspect
of addiction is withdrawal, and the symptoms of nicotine withdrawal usually
begin within hours and consist of craving, irritability, anxiety, restlessness,
and increased appetite. The craving may last for months  even years.

The psychological effects of nicotine at first seem contradic­tory:
increasing alertness while providing a sense of relaxation and calm. One
possible explanation is that the effect varies with the users initial
state. For someone whos agitated, nicotine has a calming effect.
For someone who isnt, it heightens alert­ness. This difference
may also help explain why nicotine, unlike many other addictive drugs,
doesnt behave in a simple additive manner as the dose increases.

Nicotine is addictive because it triggers a reaction in the brains
reward system, the structures responsible for giving us pleasurable sensations.
More specifically, the drug intensifies the activity of the neurotransmitter
dopamine in a part of the brain called the nucleus accumbens. Cocaine
and amphetamines do much the same thing; nicotine is tame in comparison.
But experts theorize that it may have an added effect because the drug
ampli­fies the brains response to the behaviours associated
with smoking. In other words, its not just nicotine, but the pleasur­able
sensation it confers on behaviours associated with smoking that make nicotine
so addictive.

Nicotine can be addictive without cigarette smoke. For example, people
become addicted to the nicotine in chewing tobacco and thambaku that is
tucked next to the gums. As a rule, though, most drugs of abuse are not
as addictive if they are delivered more gradually. In South America, coca
leaves are chewed or used to make tea as a mild stimulant. Whatever the
harmful effects, theyre a far cry from snorting cocaine. Methylphenidate
(Rita­lin) is chemically more or less the same drug as the injectable
amphetamines made in illicit laboratories. But in pill form for treatment
of ADHD the effects on the brain are so much milder that it changes the
character of the drug, despite the chemical similarities.

Effects outside the brain

Nicotine does have some negative cardiovascular effects, raising blood
pressure and causing arteries to constrict, but its debat­able
how significant they are. Doctors were initially quite concerned about
prescribing the nicotine patch and other so-called nicotine replacement
therapies for smokers with heart disease. But several studies in the mid-1990s
showed that the nicotine replacements didnt increase the number
of heart attacks and strokes in these high-risk patients, so those worries
have ebbed. Still, those were short-term studies, so cardiovascular harm
from long term use might be a problem.

Most experts say nicotine itself does not cause cancer. Its addictive,
which gets people hooked on cigarettes, but the pre­vailing view has
been that it is other substances in tobacco smoke (polycyclic aromatic
hydrocarbons, tobacco-specific nitro­samine) that cause DNA damage
and therefore cancer.

Nicotines imitators

Nicotine binds to the nerve cell receptors known as nicotinic or nicotinic
acetylcholine receptors. Depending on the receptor and other factors,
that binding may speed up the signaling between nerve cells or slow it
down. There are at least a dozen nicotinic receptors; their functions
are varied and overlap but often involve the processing of thoughts.

The molecules that snuggle into these receptors neednt come from
tobacco or nicotine. Dr. Paul A. Newhouse, director of the Uni­versity
of Vermonts Clinical Neuroscience Research Unit and for two decades
a leading researcher in this field, says that one set of compounds now
under investigation comes from a toxin in nemer­tine worms.

Drug companies are investing in nicotine-related compounds. Abbott Laboratories
ABT-418 has shown promise in treating ADHD. Taiho Pharmaceuticals has
licensed a drug, code-named DMXB-A (also known as GTS-21), that is in
early trials for the treatment of schizophrenia. Pfizers novel antismoking
pill, Varenicline, is supposed to turn on nicotinic receptors just enough
so smokers dont go through withdrawal, but not enough to cause addiction.

Why so slow?

Researchers have been talking about nicotine-related drugs for decades,
but none are on the market yet. Part of the problem is reputation. One
researcher has suggested that nicotinic drugs be termed "cholinergic-channel
modulators" to avoid the stigma. And it isnt just image. Nicotine
researchers have accepted money from tobacco companies. Targacept, a biopharmaceutical
firm that focuses exclusively on this area of research, was part of R.
J. Reynolds until 2000.

Even without these problems, designing nicotine-related drugs is tricky.
Researchers must find compounds that are selective. "Nicotine is
a pretty promiscuous drug," Dr. Newhouse explains. "It hits
a lot of things at once. But for effective medications, we want to target
specific receptors subtypes." Another obstacle is that nicotine-related
compounds often have a fairly narrow therapeutic index: There isnt
much difference between a dose thats helpful and one thats
toxic. That isnt insurmountable, but it slows down clinical development.

Finally, the possibility that nicotine has angiogenic properties may put a damper on the research.
In a review article on nicotine and angiogenesis published last year in
the Annals of Medicine, researchers John P. Cooke and Haim Bitterman said
there was little reason to be worried about short-term use. In their opin­ion,
nicotine gums and patches are safe and effective when "used as directed."
But they called on scientists investigating the therapeutic potential
of nicotine-like drugs to take the "potent angiogenic effects of
nicotine" into account. Dr. Newhouse says the angiogenesis evidence
comes largely from animal studies, so it doesnt necessarily apply
to humans. He also points to the good safety record of the patch and other
nicotine replacements, while noting that there has been some legitimate
concern about the development of insulin resistance.

Successful patchwork

Investigators are seeing if the nicotine patch might have other uses
besides helping smokers quit. Last year, one trial found that the patch
improved cognitive performance in patients with schizophrenia. A 2003
study investigated the effectiveness of nicotine patch therapy in nonsmoking
patients diagnosed with depression. And a 2001 study reported promising
results for treatment of Tourettes disorder with a combination of
the nico­tine patch and the antipsychotic drug haloperido.

In a 2004 Psychopharmacology article, Dr. Newhouse and Alexandra Potter,
Ph.D., reported that the high smoking rate among adoles­cents and
adults with ADHD could be explained by their discovery that nicotine improves
aspects of their mental functioning. Potter is now recruiting people for
two ADHD trials  one in­volving nicotine and the other a drug
called mecamylamine, which blocks certain nicotinic receptors.

An especially promising area of research involves cognitive impairments
that are a precursor to Alzheimers disease. Last year, Duke University
researchers published a small study on the effect of the nicotine patch
in people with such impairments. They reported significant improvement
in decision-making ability and attention (but not motor function or memory)
in 11 subjects. Those results led to a larger study funded by the National
Insti­tute on Aging.

Dr. Newhouse believes people are already using nicotine patches on their
own for memory problems. "We get e-mails and letters inquiring about
this almost every day," he says. "We still dont have the
data to recommend it. But were excited at the prospects and think
the strategy looks pretty promising."

Express Delivery

Cigarettes are addictive because they are so efficient at deliv­ering
nicotine to the brain.

1 The average smoker inhales 1-2 milligrams of nicotine per cigarette.
The brain of a pack-a-day smoker gets 200 "hits" of the drug
daily.

2 Tobacco smoke contains more than 50 known carcinogens  but most
experts say nicotine isnt one of them.

3 Nicotine goes straight into the lungs and is rapidly absorbed by the
oxygenated blood that the heart pumps throughout the body and brain.

4 The nicotine in cigarette smoke reaches the brain in just 10 seconds.

5 Nicotine stimulates the release of dopamine in the nucleus accumbens,
the brains "reward centre." Behaviours surrounding smoking
may also have an effect.